Ankita Punetha1, Huy X Ngo1, Selina Y L Holbrook1, Keith D Green1, Melisa J Willby2, Shilah A Bonnett3, Kyle Krieger3,4, Emily K Dennis1, James E Posey2, Tanya Parish3,4, Oleg V Tsodikov1, Sylvie Garneau-Tsodikova1. 1. Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky 40536-0596, United States. 2. Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, United States. 3. TB Discovery Research, Infectious Disease Research Institute, Seattle, Washington 98102, United States. 4. Center for Global Infectious Disease, Seattle Children's Research Institute, Seattle Children's Hospital, Seattle, Washington 98145, United States.
Abstract
The enhanced intracellular survival (Eis) protein of Mycobacterium tuberculosis (Mtb) is a versatile acetyltransferase that multiacetylates aminoglycoside antibiotics abolishing their binding to the bacterial ribosome. When overexpressed as a result of promoter mutations, Eis causes drug resistance. In an attempt to overcome the Eis-mediated kanamycin resistance of Mtb, we designed and optimized structurally unique thieno[2,3-d]pyrimidine Eis inhibitors toward effective kanamycin adjuvant combination therapy. We obtained 12 crystal structures of enzyme-inhibitor complexes, which guided our rational structure-based design of 72 thieno[2,3-d]pyrimidine analogues divided into three families. We evaluated the potency of these inhibitors in vitro as well as their ability to restore the activity of kanamycin in a resistant strain of Mtb, in which Eis was upregulated. Furthermore, we evaluated the metabolic stability of 11 compounds in vitro. This study showcases how structural information can guide Eis inhibitor design.
The enhanced intracellular survival (Eis) protein of n class="Species">Mycobacterium tuberculosis (Mtb) is a versatile acetyltransferase that multiacetylates aminoglycoside antibiotics abolishing their binding to the bacterial ribosome. When overexpressed as a result of promoter mutations, Eis causes drug resistance. In an attempt to overcome the Eis-mediated kanamycin resistance of Mtb, we designed and optimized structurally unique thieno[2,3-d]pyrimidineEis inhibitors toward effective kanamycin adjuvant combination therapy. We obtained 12 crystal structures of enzyme-inhibitor complexes, which guided our rational structure-based design of 72 thieno[2,3-d]pyrimidine analogues divided into three families. We evaluated the potency of these inhibitors in vitro as well as their ability to restore the activity of kanamycin in a resistant strain of Mtb, in which Eis was upregulated. Furthermore, we evaluated the metabolic stability of 11 compounds in vitro. This study showcases how structural information can guide Eis inhibitor design.
Authors: Atefeh Garzan; Melisa J Willby; Huy X Ngo; Chathurada S Gajadeera; Keith D Green; Selina Y L Holbrook; Caixia Hou; James E Posey; Oleg V Tsodikov; Sylvie Garneau-Tsodikova Journal: ACS Infect Dis Date: 2017-02-17 Impact factor: 5.084
Authors: Jacob L Houghton; Keith D Green; Rachel E Pricer; Abdelrahman S Mayhoub; Sylvie Garneau-Tsodikova Journal: J Antimicrob Chemother Date: 2012-12-11 Impact factor: 5.790
Authors: Atefeh Garzan; Melisa J Willby; Keith D Green; Chathurada S Gajadeera; Caixia Hou; Oleg V Tsodikov; James E Posey; Sylvie Garneau-Tsodikova Journal: J Med Chem Date: 2016-11-22 Impact factor: 7.446
Authors: Allan H Pang; Keith D Green; Nishad Thamban Chandrika; Atefeh Garzan; Ankita Punetha; Selina Y L Holbrook; Melisa J Willby; James E Posey; Oleg V Tsodikov; Sylvie Garneau-Tsodikova Journal: Eur J Med Chem Date: 2022-08-18 Impact factor: 7.088
Authors: Ankita Punetha; Keith D Green; Atefeh Garzan; Nishad Thamban Chandrika; Melisa J Willby; Allan H Pang; Caixia Hou; Selina Y L Holbrook; Kyle Krieger; James E Posey; Tanya Parish; Oleg V Tsodikov; Sylvie Garneau-Tsodikova Journal: RSC Med Chem Date: 2021-10-05
Authors: Haytham O Tawfik; Anwar A El-Hamaky; Eman A El-Bastawissy; Kirill A Shcherbakov; Alexander V Veselovsky; Yulia A Gladilina; Dmitry D Zhdanov; Mervat H El-Hamamsy Journal: Pharmaceuticals (Basel) Date: 2022-04-14